Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:11]=[C:10]([NH:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=2)[N:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CC(C)=O.O>[NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[N:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[N:11]=[C:10]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=2)[N:9]=1
Reactant: COC(=O)c1ccc(Nc2nc(NCCNCCN)nc(OCC(F)(F)F)n2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: NCCNCCNc1nc(Nc2ccc(C(=O)O)cc2)nc(OCC(F)(F)F)n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
To a suspension of methyl 4-(4-(2-(2-aminoethylamino)ethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.1 g) in acetone (6 mL) was added potassium carbonate (0.080 g) in water (6.00 mL). The mixture was heated to reflux for 16 hours. After cooling to room temperature, the reaction solution was acidified with 1N HCl to pH=3. All solvents were removed under vacuum. The residue was purified by prep. HPLC to give 4-(4-(2-(2-aminoethylamino)ethylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (40 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]=12)=[O:4].[CH3:26]S(C1C=CC(F)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:8]2[CH2:14][C:12]([CH3:26])([CH3:11])[O:13][C:9]=2[CH:10]=1)=[O:4]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-fluorophenyl methyl sulfone (115 mg, 0.77 mmol), Cs2CO3 (507 mg, 1.54 mmol), and methyl 6-hydroxyl-2-methyl-2,3-dihdrovenzofuran-4-carboxylate (3e) (171 mg, 0.77 mmol). Purification by column chromatography eluting with 15-40% EtOAc in hexanes gave a pale brown solid (230 mg, 79% yield). 1H NMR (400 MHz, CDCl3) δ 7.88-7.94 (m, 2 H) 7.09 (d, J=2.53 Hz, 1 H) 7.05 (d, J=8.84 Hz, 2 H) 6.66 (d, J=2.53 Hz, 1 H) 3.81 (s, 3 H) 3.07 (s, 3 H) 2.92 (s, 2 H) 1.33 (s, 6 H); LCMS for C19H20O6S m/z 377.10 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH2:20][C:19]2[C:18](=[O:21])[NH:17][C:16]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[C:14]=2[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.Cl[CH2:32][CH2:33][N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CS(C)=O.O>[C:3]([N:11]1[CH2:20][C:19]2[C:18](=[O:21])[N:17]([CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:16]3[CH:22]=[C:23]([O:28][CH3:29])[C:24]([O:26][CH3:27])=[CH:25][C:15]=3[C:14]=2[CH2:13][CH2:12]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cc2[nH]c(=O)c3c(c2cc1OC)CCN(C(=O)c1ccccc1)C3
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c3c(c(=O)n(CCN4CCCCC4)c2cc1OC)CN(C(=O)c1ccccc1)CC3
Reaction time: 0.08 h
Yield: 88.1 %

Procedure:
A suspension of 0.066 m NaH in 75 cc dimethylsulfoxide was cooled in a cold water bath and treated portionwise with 10 g (0.028 m) of 3-benzoyl-1,2,3,4-tetrahydro-8,9-dimethoxy-benzo[c][2,7]naphthyridin-5(6H)-one in 10 min. After stirring for 5 min the reaction was treated with 5.5 g (0.03 m) of N-(2-chloroethyl)piperidine hydrochloride in 2 min. After stirring an additional 2 hr the reaction was diluted with water to 800 ml to give 11.5 g of crude solid product, used as is for hydrolysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C-]#N.[Na+].C1N2CC[N:14](CC2)[CH2:13]1.ClCCl>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[N:4][C:5]([C:13]#[N:14])=[N:6][CH:7]=1
Reactant: C1CN2CCN1CC2
Reactant: Clc1ncc(Br)cn1
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: N#Cc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
A solution of 5-bromo-2-chloropyrimidine (10 g, 51.8 mmol) in dimethylsulfoxide (26 mL) was added to a mixture of sodium cyanide (2.59 g, 51.8 mmol) and triethylenediamine (1.2 g, 10.4 mmol) in dimethylsulfoxide (14 mL) and water (28 mL). The resulting mixture was stirred for 18 hours at room temperature. The mixture was then diluted with water (130 mL) and extracted with diethyl ether (3×150 mL). The combined organic solutions were dried over sodium sulfate and concentrated in vacuo to give a pale yellow solid. Re-crystallisation of the solid from hot dichloromethane afforded the title product in 99% yield, 9.4 g.
Reaction SMILES: Cl[C:2]1[C:7]([I:8])=[CH:6][N:5]=[CH:4][N:3]=1.[F:9][C:10]([F:14])([F:13])[CH2:11][NH2:12].CCN(C(C)C)C(C)C>CCO>[I:8][C:7]1[C:2]([NH:12][CH2:11][C:10]([F:14])([F:13])[F:9])=[N:3][CH:4]=[N:5][CH:6]=1
Reactant: NCC(F)(F)F
Reactant: Clc1ncncc1I
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)CNc1ncncc1I
Temperature: 120 °C
Yield: 59 %

Procedure:
To a solution of 4-chloro-5-iodopyrimidine (0.250 g, 1.040 mmol) and 2,2,2-trifluoroethanamine (0.216 g, 2.184 mmol) in EtOH (volume: 2.080 ml) was added Hunig's Base (0.200 ml, 1.144 mmol). The reaction mixture was heated in a microwave for 4 h at 120° C. and then allowed to cool to room temperature. The solvent was evaporated. The crude material was dissolved in a minimal amount of CH2Cl2 to be chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (24 g column, 35 mL/min, 0-90% EtOAc in hexanes over 25 min, ret. T=12 min) gave Intermediate 107A (0.188 g, 0.614 mmol, 59.1% yield) as a yellow residue. MS (ESI): m/z=303.9 [M+H]+ HPLC Peak ret. T=1.26 minutes was product. (HPLC conditions: Column:Luna C18 4.6×30 mm 3 u A:10:90 H2O:ACN NH4OAc/B:10:90 H2O:ACN NH4OAc; 0%-95% B in 2 min; 4 mL/min flow).
Reaction SMILES: [I:1]NC(=O)CCC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:23]([O:27][C:28]1[N:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH:24](C)[CH3:25]>FC(F)(F)C(O)=O>[CH2:23]([O:27][C:28]1[N:36]=[CH:35][C:34]([I:1])=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])[CH2:24][CH3:25]
Reactant: NC(=O)CCC(=O)NI
Reactant: CC(C)COc1ncccc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCOc1ncc(I)cc1C(=O)O

Procedure:
N-Iodosuccinamide (18.22 g, 0.08 mol), trifluoroacetic acid (100 mL) and trifluoroacetic anhydride (25 mL) were added to 2-isobutoxynicotinic acid (10.55 g, 0.054 mol). The mixture was refluxed for 2.5 h, cooled and the solvents evaporated. The residue was extracted from water with ethyl acetate and the organics washed with water (twice) and brine (twice), dried (MgSO4) and concentrated. The red residue was redissolved in ethyl acetate washed with sodium thiosulfate solution (twice), water (twice), brine (twice), redried (MgSO4) and concentrated to give the desired product as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1.C1CCCCC=1.B(Br)(Br)Br>ClCCl>[F:1][C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[CH:11]([CH3:27])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccc(F)cc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2cc(F)ccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from 2-fluoro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (220 mg, 0.57 mmol), cyclohexene (1.2 mL, 11.5 mmol), and 1.0 M solution of boron tribromide in dichloromethane (3.4 mL) according to the procedure and in the same manner as described in Example 105, step e. The volatile components were removed in vacuo, and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 5%-30% methyl tert-butyl ether in hexane, to afford the product (164 mg, 77%) as a solid, m.p. 216-218° C.;
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH:16]([OH:17])[CH:15]([Cl:18])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1.Cl>FC(F)(F)C(O)=O.CO.C(OCC)C>[ClH:18].[NH2:2][CH:3]1[C:16](=[O:17])[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]=2[CH2:4]1
Reactant: NC1Cc2ccc3ccccc3c2C(Cl)C1O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Solvent: CO
Product: NC1Cc2ccc3ccccc3c2CC1=O
Yield: 52.8 %

Procedure:
2-Amino-4-chloro-1,2,3,4-tetrahydro-3-phenanthrenol, hydrochloride (265 mg) was refluxed in trifluoroacetic acid (25 ml) for 3 hours. The green mixture was evaporated in vacuo taken up into methanol and treated with activated charcoal for 2 hours at room temperature. Filtration and evaporation yielded a yellow oil which was diluted with methanol and acidified with a solution of hydrochloric acid in diethyl ether. The mixture was evaporated and the acidification process was repeated. Evaporation gave a residue which was recrystallized in a methanol/diethyl ether mixture to afford the title compound (122 mg) as a cream colored powder.
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][C:4]#[CH:5].BrC1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1.[CH2:18](N(CC)CC)C>[Cu]I>[OH:6][C:2]([CH3:18])([CH3:1])[C:3]#[C:4][C:5]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=1
Reactant: CCN(CC)CC
Reactant: CC(=O)Cc1ccc(Br)cc1
Reactant: C#CCC(C)O
Agent: [Cu]I
Product: CC(=O)Cc1ccc(C#CC(C)(C)O)cc1
Temperature: 55 °C
Yield: 90.3 %

Procedure:
0,35 g (0,5 mmol) Pd[TPP]2Cl2 and 0.12 g (=0.6 mmol) of copper(I) iodide and, with stirring in the course of a few minutes, 10.7 g (=0.13 mmol) of 1-methyl-3-butyn-1-ol are added to a solution of 21.3 g (=0.1 mol) of 4-bromophenylacetone in 250 ml of triethylamine. The mixture is warmed to 55° C. and the temperature is allowed slowly to rise to 80° C. during the course of 4 hours. After cooling, the mixture is filtered and the filtrate is concentrated. The oil which remains is chromatographed on silica gel. 17.4 g (90.3% of theory) of 4-(3-hydroxy-3-methyl-1-butynyl)phenylacetone are obtained; m.p. 67-69° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1.C([O:12][CH:13]=[C:14]([C:20](OCC)=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.C(C1C=NC2C(C=1)=CC=C(OC1C3C(=CC(OCC4CCN(C)CC4)=C(OC)C=3)N=CN=1)C=2)#N>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:6]([C:13](=[O:12])[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][NH:9]2)=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1cccc(N)c1
Agent: COc1cc2c(Oc3ccc4cc(C#N)cnc4c3)ncnc2cc1OCC1CCN(C)CC1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2cc(OC)ccc2c1=O
Temperature: 240 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
m-Anisidine (50 g, 407 mmol) and diethyl ethoxymethylenemalonate (102 g, 407 mmol) were heated at 60° C. for 20 minutes. Diphenyl ether (270 ml) was then added and the temperature was raised to 240° C. over 30 minutes. The ethanol formed distilled off. Heating was maintained at this temperature for 1 hour then the reaction mixture was allowed to cool to 120° C. at which point the reaction mixture was diluted with heptane and allowed to stand overnight at ambient temperature. The brown solid was collected by filtration and washed with methanol and ether to give ethyl 7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (45 g, 45%). This reaction was repeated twice.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([OH:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([I:15])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[S:22]([O:32][NH2:33])([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>CN(C)C=O.ClCCl>[S:22]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([O-:32])(=[O:24])=[O:23].[NH2:33][N+:3]1[C:4]2[C:9](=[CH:8][C:7]([I:15])=[CH:6][CH:5]=2)[C:10]([OH:14])=[C:11]([C:12]#[N:13])[C:2]=1[NH2:1]
Reactant: Cc1ccc(S(=O)(=O)ON)cc1
Reactant: N#Cc1c(N)nc2ccc(I)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Product: N#Cc1c(O)c2cc(I)ccc2[n+](N)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.4 %

Procedure:
0.62 g of 2-amino-3-cyano-4-hydroxy-6-iodoquinoline is stirred for 40 minutes in 10 ml dimethylformamide in the presence of 1 g solid potassium carbonate, then the solution of 0.6 g O-tosyl-hydroxylamine in 14 ml dichloromethane is added dropwise. After stirring the reaction mixture at room temperature for 4 hours, the precipitated solid material is filtered off and dried to obtain 0.57 g of the title compound (MH+: 327).
Reaction SMILES: [C:1]1([CH:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)Cl.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[C:18]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][S:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)(=[O:42])=[O:41])[CH2:12][CH2:13]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Yield: 114.7 %

Procedure:
85 mg of 1-diphenylmethyl-4-(3-aminopropyl)-piperazine and 102.5 mg of triethylamine were added to ml of methylene chloride, and under ice cooling and stirring, 39.4 mg of benzenesulfonyl chloride was added. The mixture was further stirred at this temperature for 1 hour. Chloroform was added to the reaction mixture, and the mixture was washed with water and dried. The solvent was then evaporated to give 115 mg of the captioned compound as a crude product. It was converted to a dihydrochloride in a customary manner, and recrystallization from ethanol/ether gave 92.7 mg of the captioned compound as a colorless powdery crystal having a melting point of 160° to 165° C. (decomp.). ##STR4##
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].O>N1C=CC=CC=1>[C:1]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH:33]=[CH:32][C:30](=[O:31])[NH:29][C:27]1=[O:28])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCCCn1ccc(=O)[nH]c1=O
Solvent: O
Solvent: c1ccncc1
Product: O=c1ccn(CCCCNC(c2ccccc2)(c2ccccc2)c2ccccc2)c(=O)[nH]1
Temperature: 50 °C
Yield: 24.1 %

Procedure:
Trityl chloride (0.358 g, 1.28 mmol) was added to a solution of 1-(4′-aminobutyl)uracil (contaminated by 11% 1,3-bis(4′-aminobutyl)uracil) (0.168 g) in anhydrous pyridine (15 mL). The reaction mixture was heated at 50° C. for 44 h, left to cool to room temperature, poured into cold water (50 mL) and extracted with DCM (3×25 mL). The organic extracts were washed with brine (40 mL), dried over Na2SO4 and concentrated in vacuo. Further purification was carried out by silica gel column chromatography, using Jones Chromatography Isolute SI columns with a gradient elution of 0→5% CH3OH in CHCl3. The fractions with Rf=0.51 (10% CH3OH/CHCl3) gave the title compound as a white crystalline solid (94 mg, ca 24%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:10][CH2:11][C:12]1([C:18]#[N:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CS(C)=O>[Cl:1][C:2]1[C:3]([I:9])=[CH:4][C:5]([NH:19][CH2:18][C:12]2([C:11]#[N:10])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: Fc1cc(I)c(Cl)cn1
Reactant: N#CC1(CN)CCOCC1
Solvent: CS(C)=O
Product: N#CC1(CNc2cc(I)c(Cl)cn2)CCOCC1

Procedure:
A solution of 5-chloro-2-fluoro-4-iodopyridine (1 g, 3.88 mmol) and 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (1.634 g, 11.65 mmol) in 4 mL of dimethylsulfoxide was heated at 100° C. for 8 hours. The mixture was quenched with 100 mL of ice-cold water and was extracted with ethyl acetate (50 mL×2). The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification by column chromatography (silica gel, 20% ethyl acetate in hexane) afforded the title compound.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8].[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Cl:8])(=[O:18])=[O:19]
Reactant: Cc1noc(N)c1Cl
Reactant: Cc1ccc(C)c(S(=O)(=O)Cl)c1
Product: Cc1ccc(C)c(S(=O)(=O)Nc2onc(C)c2Cl)c1
Yield: 82 %

Procedure:
2,5-Dimethyl-N-(4-chloro-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-chloro-3-methylisoxazole and 2,5-dimethylbenzenesulfonyl chloride according to the procedures described in Example 25b. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a light yellow solid, m.p. 92-93° C., yield 82%.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19](Cl)[N:18]=[C:17]([S:28][CH3:29])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:30][CH2:31][CH2:32][OH:33]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]([O:33][CH2:32][CH2:31][NH2:30])[N:18]=[C:17]([S:28][CH3:29])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: CSc1nc(Cl)c(-c2ccccc2)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)n1
Product: CSc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(-c2ccccc2)c(OCCN)n1

Procedure:
4.0 g 4-tert.-butyl-N-(6-chloro-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl) -benzenesulfonamide was reacted with 2-aminoethanol according to Example 4b) to give 1.65 g 4-tert.-butyl-N-[6-(2-aminoethoxy)-2-methylsulfanyl-5-phenyl-pyrimidin-4-yl]-benzenesulfonamide. LC-MS: tR=3.75 min, [M−1]−=471.38.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[Cl:27]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:26])[C@@H:5]([CH2:12][C:13]1[CH:18]=[C:17]([Cl:27])[C:16]([NH2:19])=[C:15]([CH3:20])[C:14]=1[CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2]
Reactant: CCOC(=O)C[C@H](Cc1ccc(N)c(C)c1COC(C)=O)C(=O)OCC
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C[C@H](Cc1cc(Cl)c(N)c(C)c1COC(C)=O)C(=O)OCC
Temperature: 60 °C
Yield: 59 %

Procedure:
2-(S)-(2-Acetoxymethyl-4-amino-3-methyl-benzyl)-succinic acid diethyl ester (3.0 g, 8.2 mmol) was dissolved in acetonitrile (40 mL). Mixture was warmed to 60° C. N-Chlorosuccinimide (1.29 g, 9.7 mmol) was added to the warm solution. Reaction mixture was heated at reflux for 10 minutes. Mixture was cooled to room temperature then diluted with ethyl acetate (20 mL). Mixture was washed successively with saturated aqueous sodium bicarbonate (40 mL), and brine (20 mL). Organic was dried (magnesium sulfate), filtered and concentrated in vacuo. Silica gel chromatography (ethyl acetate-hexanes) afforded the desired product in 59% yield as an amber oil. 1H NMR (300 MHz, CDCl3): δ=6.98 (s, 1H), 5.15 (d, J=3.3, 2H), 4.09 (m, 4H), 2.99 (m, 2H), 2.69 (m, 2H), 2.39 (dd, J1=4.8, J2=16.5, 1H), 2.17 (s, 3H), 2.06 (s, 3H), 1.20 (m, 6H). MS m/e (M−C2H4O2+H)+=340.0.
Reaction SMILES: P(Br)(Br)[Br:2].[Cl:5][C:6]1[C:7]([CH3:14])=[C:8]([CH2:12]O)[CH:9]=[CH:10][CH:11]=1>C1(C)C=CC=CC=1>[Br:2][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[CH3:14]
Reactant: Cc1c(Cl)cccc1CO
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cccc1CBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 203.8 %

Procedure:
To a solution of phosphorus tribromide (0.422 mL, 4.47 mmol) in Toluene (30 mL) was added (3-chloro-2-methylphenyl)methanol (2 g, 12.77 mmol). The reaction was stirred at RT overnight. The solvent was removed and the residue was partitioned between EtOAc and brine. The organic layer was concentrated and the residue was purified by biotage (5% EA/hexane) to give the product (2.0 g, 71%). 1H NMR (400 MHz, CDCl3) δppm 7.36 (m, 1H), 7.24 (m, 1H), 7.12 (m, 1H), 4.56 (s, 2H). 2.48 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][C:9]=1[C:17]([F:20])([F:19])[F:18].[NH2:21][C:22](=[N:34][OH:35])[C:23]1[CH:24]=[CH:25][C:26]([F:33])=[C:27]([CH:32]=1)[C:28]([O:30][CH3:31])=[O:29]>>[F:33][C:26]1[CH:25]=[CH:24][C:23]([C:22]2[N:21]=[C:12]([C:11]3[CH:15]=[CH:16][C:8]([N:3]4[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]4[CH3:1])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:10]=3)[O:35][N:34]=2)=[CH:32][C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Reactant: COC(=O)c1cc(C(N)=NO)ccc1F
Product: COC(=O)c1cc(-c2noc(-c3ccc(N4CCCCC4C)c(C(F)(F)F)c3)n2)ccc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 15 (106.09 mg; 0.50 mmol) and Intermediate 45 (106.09 mg; 0.50 mmol). The reaction mixture was filtered through a SPE NH2 column (2 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (2 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/EtOAc: 9.5/0.5), affording the title compound. 1H NMR (DMSO-d6, 300 MHz) δ 8.58 (dd, J=7.0, 2.3 Hz, 1H), 8.46 (dd, J=8.3, 2.1 Hz, 1H), 8.41-8.36 (m, 2H), 7.87 (d, J=8.4 Hz, 1H), 7.62 (dd, 1H), 3.93 (s, 3H), 3.23-3.14 (m, 1H), 2.99-2.92 (m, 1H), 2.66-2.58 (m, 1H), 1.82-1.75 (m, 2H), 1.67-1.30 (m, 4H), 0.79 (d, J=6.1 Hz, 3H). LC/MS (Method B): 464.3 (M+H)+. HPLC (Method A) Rt 3.82 min (Purity: 99.9%).
Reaction SMILES: NC1C=C(C=CC=1)OC1C=CC(C2N=C(C3CCC3)N3C=CN=C(N)C=23)=CC=1.[CH:29]1([C:33]2[N:37]3[CH:38]=[CH:39][N:40]=[C:41]([NH2:42])[C:36]3=[C:35]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)=[C:45]([N+:56]([O-])=O)[CH:44]=3)[N:34]=2)[CH2:32][CH2:31][CH2:30]1>>[NH2:56][C:45]1[CH:44]=[C:43]([C:35]2[N:34]=[C:33]([CH:29]3[CH2:32][CH2:31][CH2:30]3)[N:37]3[CH:38]=[CH:39][N:40]=[C:41]([NH2:42])[C:36]=23)[CH:48]=[CH:47][C:46]=1[O:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Nc1nccn2c(C3CCC3)nc(-c3ccc(Oc4ccccc4)c([N+](=O)[O-])c3)c12
Agent: Nc1cccc(Oc2ccc(-c3nc(C4CCC4)n4ccnc(N)c34)cc2)c1
Product: Nc1cc(-c2nc(C3CCC3)n3ccnc(N)c23)ccc1Oc1ccccc1

Procedure:
Prepared according to a procedure analogous to that described for 1-[4-(3-aminophenoxy)-phenyl]-3-cyclobutylimidazo[1,5-a]pyrazin-8-ylamine, except using 3-cyclobutyl-1-(3-nitro-4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-8-ylamine.